1. Field of the Invention
This invention relates to reduction of 1.alpha.,2.alpha.-epoxy-steroid-4,6-dien-3-ones directly to the corresponding 1.alpha.,3.beta.-dihydroxy-steroid-5-enes.
2. Description of the Prior Art
1.alpha.,3.beta.-Dihydroxy-steroid-5-enes are useful intermediates in the synthesis of 1.alpha.-hydroxy vitamin D derivatives.
Barton et al, J.A.C.S. 95:8, 2748 (1973) describe reduction of 1.alpha.,2.alpha.-epoxycholesta-4,6-dien-3-one with large excesses of each of lithium metal and ammonium chloride in ammonia/tetrahydrofuran at reflux to obtain 1.alpha.,3.beta.-dihydroxycholest-5-ene which is a precursor of 1.alpha.-hydroxyvitamin D.sub.3.
U.S. Pat. No. 3,901,928 -- Hesse et al, issued Aug. 26, 1975, describe direct reduction of 1.alpha.-hydroxy-and 1.alpha.,2.alpha.-epoxy-steroid-4,6-dien-3-ones and corresponding 6-substituted steroid-4-en-3-ones, where the 6-substituent is a reductively eliminatable atom or group, to the corresponding 1.alpha.,3.beta.-dihydroxy-steroid-5-ene by reaction with an alkali metal/liquid ammonia or alkali metal/liquid amine reducing agent in the presence of a proton source such as ammonium chloride.
These references utilize various modes of addition to bring the reactants together. For example, a solution of the steroid is added in one or more portions to a solution of the alkali metal in liquid ammonia or a liquid amine, with subsequent addition in one or more portions of the proton source.
Alternatively, improved yields and/or greater ease of isolation of the reduced steroid are claimed if the proton source is initially present in the solution of the steroid starting material in liquid ammonia or liquid amine and the reducing agent is then added in portions. However, these procedures produce 6-ene compounds rather than the desired 5-ene compounds.
U.S. Pat. No. 3,966,777 -- Mazur et al, issued June 29, 1976, describe adding 1.alpha.,2.alpha.-epoxycholesta-4,6-dien-3-one dissolved in a suitable solvent at a low temperature (of about -30.degree. C.) to liquid ammonia, then adding ammonium chloride followed by lithium metal. Suitable solvents include ethers, such as tetrahydrofuran. An excess of ammonium chloride is added and is followed by addition of an excess of lithium. The ammonia chloride and lithium metal additions are repeated several times, usually between 4 and 7 times. The principal product is the undesired 1.alpha.,3.beta.-dihydroxycholest-6-ene which is obtained in a yield of about 50 percent.
Improved processes for these useful dihydroxy steroid-5-ene intermediates are needed in the synthesis of 1.alpha.-hydroxyvitamin D derivatives.